Recurrent major depression (rMD) is a complex, common, costly, and often impairing disorder. Although there are overwhelming data that genetic factors have an important etiological role, no susceptibility loci have been convincingly identified or localized in humans. There are probably multiple loci of modest individual effect. The goal of this resubmission is to identify one or more such loci for rMD. To accomplish this goal, we will capitalize on the strong genetic and phenotypic relationship between rMD and the quantitative personality trait of neuroticism. This strong relationship enables the application of bivariate selection of sibling pairs with extreme combinations of rMD and neuroticism, whose power is well-supported by simulation and animal studies. We propose to screen (by mail) and follow-up (by mail and telephone) 100,000 adult members of an existing twin registry for rMD and neuroticism and then to collect DNA samples from 1,800 extreme pairs (plus all available parents) defined by bivariate selection on rMD and neuroticism. We will then use an efficient split-sample, grid-tightening genotyping strategy to genotype half the sample at an average 10 cM marker gap and follow-up five regions with a 2.5 cM fine grid in the entire sample. Joint multipoint analyses of these data are tractable and we show that our approach possesses equal to or >80% power to detect linkage to a quantitative trait locus accounting for as little as 10% of the phenotypic variance in liability to rMD. For functional and positional candidate genes, case-control and family-based tests of linkage disequilibrium are particularly powerful and may be able to detect effects accounting for as little as 1% of the trait variance. Compared to the initial submission, this resubmission is more programmatic and will do more phenotyping and genotyping, possess greater power, and yet cost less. The long-term goal of this program of research is to use molecular genetic techniques to identify the brain mechanisms responsible for susceptibility to rMD. Given its public health importance, it is imperative that we make a serious attempt to accomplish this goal as identification of susceptibility loci could lead to dramatic improvements in the treatment and prevention of rMD.